Tumor necrosis factor-alpha (TNFalpha) induces multiple physiological effects through distinct signaling cascades associated with TNF receptor-type I (TNFR1) and -type II (TNFR2). TNFalpha plays an important role in the pathogenesis of inflammatory bowel disease (IBD) and neutralization of TNFalpha is effective in the treatment of Crohn's disease (CD). TNFR2 can be expressed by inflammatory cells including lymphocytes and macrophages as well as colonic epithelial cells (CEC) under inflammatory conditions, and the induction of TNFR2 expression on CEC is associated with the development of IBD. TNFR1 which is constitutively expressed on the CEC seems to be involved in the regulation of TNFR2 expression. The experiments in the proposal are designed to test the hypothesis that TNFalpha/TNFRs interactions on CEC play functionally distinct roles from those on immune cells in the development of colitis. We also hypothesize that the TNFRs mediate different responses in T helper type 1 (Th1)- and T helper type 2 (Th2)-dominant chronic colitis. In Aim I, we plan to define the cooperative effect of TNFR1 and TNFR2 on the CEC proliferation in the context of experimental inflammation. In Aim II, we plan to define the role of TNFR2 on CEC and macrophages in the development of Th1-mediated colitis. In Aim III, we plan to define the role of TNFRs on CEC in the pathogenesis of Th2-mediated chronic colitis. These studies will help clarify the functional role of TNF/TNFRs interaction on CEC in the pathogenesis of IBD. This application is for a Mentored Clinical Scientist Development Award to an applicant who has completed training in internal medicine, and has received pre-and post-doctoral training in Immunology and immunopathology. The applicant's long term goals are to establish and direct her own independent basic research program in studies to link epithelial biology in inflammatory bowel disease. Accordingly, these studies are sponsored by Dr. Daniel K. Podolsky from the Division of Gastroenterology and by Dr. Atul K. Bhan from the Immunopathology Unit, both at Massachusetts General Hospital and Harvard Medical School.